Predicting the On-Study Relapse Rate for Multiple Sclerosis Patients in Clinical Trials

Background: The annual relapse rate has been commonly used as a primary efficacy endpoint in phase III multiple sclerosis (MS) clinical trials. The aim of this study was to determine the relative contribution of different possible prognostic factors available at baseline to the on-study relapse rate in MS. Methods: A total of 821 patients from the placebo arms of the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database were available for this analysis. The univariate relationships between on-study relapse rate and the baseline demographic, clinical, and MRI-based predictors were assessed. The multiple relationships were then examined using a Poisson regression model. Two predictor subsets were selected. Subset 1 included age at disease onset, disease duration, gender, Expanded Disability Status Scale (EDSS) at baseline, number of relapses in the last 24 months prior to baseline, and the disease course (RR and SP). Subset 2 consisted of Subset 1 plus gadolinium enhancement status in MRI. The number of patients for developing the models with no missing values was 727 for Subset 1 and 306 for Subset 2. Results:The univariate relationships show that the on-study relapse rate was higher for younger and for female patients, for RR patients than for SP patients, and for patients with positive enhancement status at entry (Wilcoxon test, p<0.05). A higher on-study relapse rate was associated with a shorter disease duration, lower entry EDSS, more pre-study relapses and more enhancing lesions in T1 at entry. The fitted Poisson model shows that disease duration (estimate=-0.02) and previous relapse number (estimate=0.59 for 1, 0.91 for 2 and 1.45 for 3 or more relapses vs 0 relapse) remain. We were able to confirm these findings in a second, independent dataset. Conclusions: The relapse number prior to entry into clinical trials together with disease duration are the best predictors for the on-study relapse rate. Disease course and gadolinium enhancement status, given the other covariates, have no significant influence on the on-study relapse rate

Phenological response of vegetation to upstream river flow in the Heihe Rive basin by time series analysis of MODIS data

Liquid and solid precipitation is abundant in the high elevation, upper reach of the Heihe River basin in northwestern China. The development of modern irrigation schemes in the middle reach of the basin is taking up an increasing share of fresh water resources, endangering the oasis and traditional irrigation systems in the lower reach. In this study, the response of vegetation in the Ejina Oasis in the lower reach of the Heihe River to the water yield of the upper catchment was analyzed by time series analysis of monthly observations of precipitation in the upper and lower catchment, river streamflow downstream of the modern irrigation schemes and satellite observations of vegetation index. Firstly, remotely sensed NDVI data acquired by Terra-MODIS are used to monitor the vegetation dynamic for a seven years period between 2000 and 2006. Due to cloud-contamination, atmospheric influence and different solar and viewing angles, however, the quality and consistence of time series of remotely sensed NDVI data are degraded. A Fourier Transform method – the Harmonic Analysis of Time Series (HANTS) algorithm – is used to reconstruct cloud- and noise-free NDVI time series data from the Terra-MODIS NDVI dataset. Modification is made on HANTS by adding additional parameters to deal with large data gaps in yearly time series in combination with a Temporal-Similarity-Statistics (TSS) method developed in this study to seek for initial values for the large gap periods. Secondly, the same Fourier Transform method is used to model time series of the vegetation phenology. The reconstructed cloud-free NDVI time series data are used to study the relationship between the water availability (i.e. the local precipitation and upstream water yield) and the evolution of vegetation conditions in Ejina Oasis from 2000 to 2006. Anomalies in precipitation, streamflow, and vegetation index are detected by comparing each year with the average year. The results showed that: the previous year total runoff had a significant relationship with the vegetation growth in Ejina Oasis and that anomalies in the spring monthly runoff of the Heihe River influenced the phenology of vegetation in the entire oasis. Warmer climate expressed by the degree-days showed positive influence on the vegetation phenology in particular during drier years. The time of maximum green-up is uniform throughout the oasis during wetter years, but showed a clear S-N gradient (downstream) during drier years

Phase-reference VLBI Observations of the Compact Steep-Spectrum Source 3C 138

We investigate a phase-reference VLBI observation that was conducted at 15.4 GHz by fast switching VLBA antennas between the compact steep-spectrum radio source 3C 138 and the quasar PKS 0528+134 which are about 4$^\circ$ away on the sky. By comparing the phase-reference mapping with the conventional hybrid mapping, we demonstrate the feasibility of high precision astrometric measurements for sources separated by 4$^\circ$. VLBI phase-reference mapping preserves the relative phase information, and thus provides an accurate relative position between 3C 138 and PKS 0528+134 of $\Delta\alpha=-9^m46^s.531000\pm0^s.000003$ and $\Delta\delta=3^\circ6^\prime26^{\prime\prime}.90311\pm0^{\prime\prime}.00007$ (J2000.0) in right ascension and declination, respectively. This gives an improved position of the nucleus (component A) of 3C 138 in J2000.0 to be RA=$05^h 21^m 9^s.885748$ and Dec=$16^\circ 38' 22''.05261$ under the assumption that the position of calibrator PKS 0528+134 is correct. We further made a hybrid map by performing several iterations of CLEAN and self-calibration on the phase-referenced data with the phase-reference map as an input model for the first phase self-calibration. Compared with the hybrid map from the limited visibility data directly obtained from fringe fitting 3C 138 data, this map has a similar dynamic range, but a higher angular resolution. Therefore, phase-reference technique is not only a means of phase connection, but also a means of increasing phase coherence time allowing self-calibration technique to be applied to much weaker sources.Comment: 9 pages plus 2 figures, accepted by PASJ (Vol.58 No.6

The structure, energy, and electronic states of vacancies in Ge nanocrystals

The atomic structure, energy of formation, and electronic states of vacancies in H-passivated Ge nanocrystals are studied by density functional theory (DFT) methods. The competition between quantum self-purification and the free surface relaxations is investigated. The free surfaces of crystals smaller than 2 nm distort the Jahn-Teller relaxation and enhance the reconstruction bonds. This increases the energy splitting of the quantum states and reduces the energy of formation to as low as 1 eV per defect in the smallest nanocrystals. In crystals larger than 2 nm the observed symmetry of the Jahn-Teller distortion matches the symmetry expected for bulk Ge crystals. Near the nanocrystal's surface the vacancy is found to have an energy of formation no larger than 0.5 to 1.4 eV per defect, but a vacancy more than 0.7 nm inside the surface has an energy of formation that is the same as in bulk Ge. No evidence of the self-purification effect is observed; the dominant effect is the free surface relaxations, which allow for the enhanced reconstruction. From the evidence in this paper, it is predicted that for moderate sized Ge nanocrystals a vacancy inside the crystal will behave bulk-like and not interact strongly with the surface, except when it is within 0.7 nm of the surface.Comment: In Press at Phys. Rev.